Natural macrolides
Historically, natural drugs were the first to appear in clinical practice. A prominent representative is oleandomycin, produced by Streptomyces antibioticus. Its antimicrobial spectrum is close to erythromycin, but it is inferior in potency. Because of this, the drug requires frequent administration (4–6 times a day). To slow down the development of bacterial resistance, oleandomycin is often used in combination with tetracycline — this drug is known as «Oletetrin».
Special attention should be paid to natural 16-membered macrolides (spiramycin, josamycin, midecamycin). Their main clinical advantages:
- They retain activity against strains of staphylococci and streptococci that have already developed resistance to erythromycin.
- They have better tolerability (significantly less likely to cause dyspeptic disorders).
- They have stable bioavailability, as food intake has practically no effect on their absorption.
Spiramycin (prescribed 2–3 times a day) is actively used in dentistry to treat gingivitis and periodontal infections. It is also the drug of choice for toxoplasmosis. Josamycin and midecamycin are taken every 8 hours. Interestingly, midecamycin acetate is a semi-synthetic prodrug: it is absorbed and penetrates tissues much more efficiently than its native form.
Semi-synthetic 14-membered macrolides
This group includes roxithromycin and clarithromycin. Their molecules were modified to solve the main problem of early macrolides — unstable pharmacokinetics.
The new drugs are perfectly absorbed from the gastrointestinal tract regardless of food intake, achieve high tissue concentrations, and have a prolonged action. This makes the dosing regimen more convenient for the patient: roxithromycin is taken 1–2 times a day, and clarithromycin is taken every 12 hours (available for both oral and intravenous administration).
Clarithromycin has a number of specific indications:
- Eradication of Helicobacter pylori in peptic ulcer disease.
- Treatment and prevention of opportunistic infections in HIV-infected patients (specifically those caused by Mycobacterium avium).
- Treatment of infections caused by intracellular pathogens (mycoplasma, chlamydia, legionella).
Azalides (Azithromycin)
Azithromycin is a 15-membered semi-synthetic macrolide. Because a nitrogen atom is incorporated into its lactone ring, the drug is classified into a separate structural subclass — azalides.
Compared to erythromycin, the spectrum of activity of azithromycin is shifted: it is less active against staphylococci, but demonstrates higher efficacy against Gram-negative flora (Enterobacteriaceae, Haemophilus influenzae) and intracellular agents (Toxoplasma, Legionella).
The pharmacokinetics of azithromycin is unique. It achieves record tissue concentrations among all representatives of the group, and its half-life ranges from 35 to 55 hours. The main clinical advantage of such kinetics is the ability to prescribe the antibiotic just once a day.
Side effects
Despite the fact that macrolides are considered the safest antibacterials, their administration may be accompanied by characteristic adverse reactions. Typical side effects include:
- Allergic reactions of varying severity.
- Dyspeptic disorders: patients often complain of nausea and a feeling of heaviness in the epigastrium. This is due to the fact that the drugs can stimulate gastrointestinal motility.
- Hepatotoxicity: development of cholestatic hepatitis and an increase in blood plasma transaminases are possible.
- Ototoxicity: in rare cases, the drugs may cause hearing impairment.
Briefly: answers to topical questions
What is the mechanism of the antibacterial action of macrolides?
The mechanism of action of macrolides is based on the disruption of intracellular protein synthesis at the ribosomal level, which provides a bacteriostatic effect.
- Molecular target — the 50S subunit of the bacterial ribosome.
- Site of action — the translocation step (the ribosome cannot move along the mRNA by one codon).
- Pathogenesis — the drug binds to a ligand inside the ribosomal tunnel, blocking the movement of the peptide from the A-site to the P-site and the release of synthesized peptides.
There is also a blockade of the enzyme peptidyl transferase, which leads to the termination of peptide chain elongation.
Which macrolides are approved for use during pregnancy?
Sources explicitly indicate spiramycin as the baseline treatment for acute toxoplasmosis in pregnant women. In chlamydial infection, systemic antibacterial therapy is possible at any stage of pregnancy, taking into account the effects on the fetus. For macrolides, especially erythromycin, an association between use during pregnancy and adverse outcomes in children has been described.
Which antibiotics belong to natural 14-membered macrolides?
Natural 14-membered macrolides include erythromycin and oleandomycin.
- Erythromycin — the baseline drug of the group, with which other macrolides are compared.
- Oleandomycin — an antibiotic produced by Streptomyces antibioticus. It is close to erythromycin in its spectrum of antimicrobial activity, but inferior to it in potency. It is used 4–6 times a day, including as part of the combination drug «Oletetrin» (with tetracycline) to slow down the development of microbial resistance.
Which macrolides are inhibitors of cytochrome P450 enzymes?
Inhibitors of the cytochrome P-450 enzyme system are the macrolides erythromycin and clarithromycin. They suppress the activity of the following isoenzymes:
- CYP3A4/3A5 — slow down the metabolism of warfarin (risk of bleeding) and other drugs.
- CYP1A2 — reduce enzyme activity, which can lead to an increased concentration of substrates in the blood.
Inhibition of microsomal enzymes slows down the metabolism of other drugs that use this pathway, increasing their blood concentration and the risk of toxic effects.
To remember typical side effects of macrolides, use the acronym «ADGO»: Allergy, Dyspepsia (motility stimulation), Hepatotoxicity (cholestatic hepatitis), Ototoxicity (hearing impairment).
Class and exam questions
What is the main difference between semisynthetic macrolides and erythromycin?
They have improved pharmacokinetics: they are excellently absorbed in the gastrointestinal tract regardless of food intake, create high tissue concentrations, and act longer, allowing less frequent administration.
Why is azithromycin classified into a separate subgroup?
Azithromycin belongs to azalides. Its chemical structure is distinguished by the presence of a nitrogen atom in the 15-membered lactone ring, which ensures record-breaking tissue accumulation and a very long half-life.
Why is oleandomycin combined with tetracycline?
This combination (the drug «Oletetrin») is used to slow down the development of microbial resistance, which occurs much faster with monotherapy using each of these antibiotics.
Which macrolide is safe for treating toxoplasmosis in pregnant women?
The drug of choice in this case is the natural 16-membered macrolide spiramycin.
What else to study on this topic
- Mechanism of Helicobacter pylori eradication by clarithromycin
- Pharmacokinetics of prodrugs using midecamycin acetate as an example
- Features of the treatment of opportunistic infections in HIV
- Mechanisms of cholestatic hepatitis development during macrolide intake
- Comparative activity of macrolides against Gram-negative flora
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